Bacterial lung infection is a major problem and may become life threatening for patients suffering from chronic lung disorders, such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease.
Specifically, cystic fibrosis (CF) is an autosomal recessive hereditary disease that affects approximately 30,000 people in the United States and approximately 40,000 in Europe. CF mutations occur in the gene encoding a chloride channel protein called the CF transmembrane conductance regulator (CFTR). Patients homozygous for defective CFTR genes typically suffer from chronic recurrent endobronchial infections (ultimately fatal) and sinusitis, as well as malabsorption due to pancreatic insufficiency, increased salt loss in sweat, obstructive hepatobiliary disease, and reduced fertility.
Pseudomonas aeruginosa (Pa) is the most significant pathogen in CF lung disease. Over 80% of CF patients eventually become colonized with Pa and the development of chronic infection of the lung with Pseudomonas aeruginosa is a typical feature of cystic fibrosis, which may induce further damage to the lung tissue and respiratory insufficiency, which is life threatening.
Tobramycin is an aminoglycoside antibiotic naturally produced by Streptomyces tenebrarius. It acts primarily by disrupting protein synthesis leading to altered cell membrane permeability, progressive disruption of the cell envelope and eventual cell death. Tobramycin is bactericidal at concentrations are equal to or slightly greater than its inhibitory concentrations.
To prevent and treat lung infections in patients with chronic lung disorders, antibiotics, such as aminoglycoside antibiotics, are widely used. Parenteral aminoglycosides are highly polar agents and penetrate poorly into the endobronchial space. Furthermore, aminoglycoside binding to sputum (International Cystic Fibrosis [Mucoviscidosis] Association, 1995 Annual Questionnaire, Paris, France; 1995, Collins F S., “Cystic fibrosis molecular biology and therapeutic implications”, Science 1992; 256, pp 774-779, Davis P B, et al., “Cystic fibrosis”, Amer J. Respir Crit Care Med 1996; 154(5), pp. 1229-56 or to sputum glycoproteins or DNA (Koch C, Hoiby N., “Pathogenesis of cystic fibrosis”, Lancet 1993; 341(8852, pp. 1065-1069) reduces bioactivity and requires local concentrations 10- to 25-fold above the minimal inhibitory concentration (MIC) to overcome reduced aminoglycoside availability to bacterial targets. To obtain adequate drug concentrations at the site of infection with parenteral administration, serum levels approach the levels associated with severe side effects such as nephrotoxicity, vestibulotoxicity, and ototoxicity (Konstan M W, Berger M. Infection and inflammation of the lung in cystic fibrosis. New York, N.Y. Dekker; 1993, FitzSimmons S C, The changing epidemiology of cystic fibrosis. J Pediatr 1993; 122:1-9).
Aerosolized administration of aminoglycosides offers an attractive alternative to parenteral administration, delivering high concentrations of antibiotic directly to the site of infection in the endobronchial space, while minimizing systemic bioavailability.
Aminoglycosides such as Tobramycin are often aerosolized using a nebulizer, i.e., an energy powered device that converts a liquid aminoglycoside formulation into a mist, which is then administered to the patient by breathing the formed mist into the lungs through a face mask or mount piece. A commonly used nebulizer for administration of aerosol formulations is the Jet nebulizer, also called “atomizers”. Jet nebulizers are connected by tubing to a compressor that causes compressed air or oxygen to blast at high velocity through a liquid medicine to turn it into an aerosol to be inhaled by the patient.
Jet nebulizers are also used for the administration of a commercially available formulation of Tobramycin solution for inhalation (TOBI®; 60 mg/mL in 5 mL of ¼ normal saline), developed by PathoGenesis Corporation (now Novartis). TOBI® was approved by the US Food and Drug Administration in 1997 for twice-daily use in CF patients over 6 years of age.
Various formulations of Tobramycin solutions for inhalation are also described in the prior art. For example, U.S. Pat. No. 5,508,269 discloses a formulation comprising from 40-100 mg of aminoglycoside in 1 ml of saline diluted into a quarter normal saline strength, wherein the formulation has a pH between 5.5 and 6.5, and wherein the solution is delivered in a 5 ml concentrated form by aerosolization.
U.S. Pat. No. 6,987,094 discloses an aerosol formulation consisting of 75 mg/ml of Tobramycin dissolved in an aqueous solution containing 0.45% w/v sodium chloride, wherein the pH is between 4.0 and 5.5, and the osmolarity ranges between 250 and 450 mOsm/l.
US patent publication 2007/0116649 suggests aerosol formulations comprising from about 100 mg/ml to 200 mg/ml of anti-gram-negative antibiotics. Tobramycin formulations are suggested, but no experiments with Tobramycin are disclosed.
US patent publication 2007/0071686 discloses a Tobramycin composition comprising about 80-120 mg/ml Tobramycin, an acidic adjuvant, and only a low concentration of sodium chloride. The acidic adjuvant may be sodium sulphate or sodium phosphate. According to US 2007/0071686, the concentration of the active agent should not exceed 120 mg/ml as higher concentrations of Tobramycin are said to have a negative effect on nebulization due to the viscosity of the composition. Furthermore, the Tobramycin composition according to US 2007/0071686 is to be administered to the patient by the use of a nebulizer, i.e., the active ingredient is inhaled by tidal breathing.
EP 2186508 describes, inter alia, a composition of less than 4 ml of a solution comprising 60-200 mg/ml aminoglycoside antibiotic in a physiologically acceptable carrier. The experiments reported in EP 2186508 show that the time necessary for administering a composition comprising 120 mg/ml Tobramycin using PART LC PLUS™ jet nebulizer (Pari Boy N compressor, Starnberg, Germany) is about 10 min. Although this might be less than the time required for administering commercial available TOBI®, the time required it still too long from a patient compliance and patient user-friendly point of view. Using a breath actuated inhalation device, EP 2186508 reports of faster administration time than that achieved with the mentioned commercially available system. However, the administration time achieved with the breath actuated inhalation device used (AcroDose™) in the experiments reported in EP 2186508 is obtained using a composition having a low Tobramycin concentration (only 60 mg/ml). It is furthermore reported that with the administration of a 60 mg/ml composition using the AcroDose™ system, a second aliquot may have to be administered as well. The need for filling and administration of a second aliquot represent a disadvantage from a patient friendly and compliance point of view.
Tobramycin solutions are also known for topical administration, e.g., in the treatment of keratitis; cf. Davis et al. (1978), Canad. J Ophtal., 13:273, 1978, Davis et al., 1978, Arch Opthalmol, vol 96, page 123-125, and Unterman et al. (1988), J. Cataract Refract. Surg., vol. 14, page 500-504.
A well-known drawback with the available administration means and treatment regimes is the time required for administration, affecting inter alia patient compliance and the patient's quality of life.
Dopfer et al., “Inhalation of Tobramycin in patients with cystic fibrosis: Comparison of two methods”, Journal of Physiology and Pharmacology, 2007, 58, suppl. 5, pp. 141-154, reports the results of a monocentric, open label, cross-over study wherein various amounts of Tobramycin (TOBI®) was administered using different inhalations systems, i.e., the well known PARI-LC PLUS® nebulizer (Pari Boy N compressor, Starnberg, Germany) and AKITA® combined with PARI LC PLUS® nebulizer (Activaero, Gemüden, Germany). The study showed that by using the AKITA® system, the time required for aerosol inhalation was reduced from about 20 minutes to about 7-8 minutes. The study further showed that similar serum concentrations were obtained by the two methods of said clinical study.
Although the use of the AKITA® administration device reduces the time needed for administration of an effective dose of Tobramycin compared with the common administration system, the time needed is still too long. There is therefore still a need for a treatment regime ensuring shorter administration times resulting in better compliance and quality of life for cystic fibrosis patients and patients having other lung disorders being treatable with Tobramycin.
In addition, the prior art systems and methods for administering aminoglycosides to the lung of a patient by inhalation suffer from further drawbacks such as that the amount of active ingredients not reaching the site of action due to the fact that remnants of the formulations remain in the nebulizer device after administration of the Tobramycin formulation or disappear out in the surroundings of the patients. From an economical and environmental point of view, there is thus also a need for administration regimes wherein lower amounts of the Tobramycin formulation are wasted.
It is therefore an object of the present disclosure to provide an improved administration regime for aminoglycosides which are not encumbered with the drawbacks of the prior art.